Atrial fibrillation (AF) is the most frequently observed type of cardiac arrhythmia and is generally identified clinically when taking a pulse and can be further confirmed with an electrocardiogram (ECG). AF causes cardiogenic cerebral embolism, and is therefore recognized as an arrhythmia that greatly affects vital prognoses and quality of life. It is known that the onset of AF increases with age, and that repeated AF strokes lead to chronic AF (The Journal of American Medical Association, 285:2370-2375 (2001) and Circulation, 114:119-123 (2006)).
The cardiac repolarization process is regulated by several outward currents, of which the ultrarapid delayed rectifier potassium current (IKur) is thought to play a major role. This current is absent in the ventricles and hence represents a suitable target for selectively modulating action potentials (APs) in the atria (Wang. Z. et al., “Sustained depolarization-induced outward current in human atrial myocytes: evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channels currents”, Circ Res., 73:1061-1076 (1993); Courtemanche, M. et al., “Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model”, Cardiovasc Res., 42:477-489 (1999); and Nattel, S., “New ideas about atrial fibrillation 50 years on”, Nature, 415:219-226 (2002)).
The ultra-rapidly activating delayed rectifier K+ current (IKur) is believed to represent the native counterpart to a cloned potassium channel designated Kv1.5 and, while present in human atrium, it appears to be absent in human ventricle. Additionally, because of its rapidity of activation and limited slow inactivation, IKur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of IKur, that is a compound which blocks Kv1.5, would overcome the short coming of other compounds by prolonging refractoriness by retarding repolarization in the human atrium without causing the delays in ventricular repolarization that underlie arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III antiarrhythmic agents. An improved agent for the prevention and treatment of AF should prolong atrial refractory period and maintain normal sinus rate without affecting the ventricle.
PCT publication number WO 2011/028741 A1 discloses compounds useful as inhibitors of potassium channel function which are used for the treatment and prevention of arrhythmia, IKur-associated disorders. The contents of this PCT publication are incorporated herein by reference.
The IKur inhibitor compounds may show pH-dependent solubility and pH-dependent bioavailability. To mitigate the long-term developability risk of reduced bioavailability in patients with concomitant gastric acid suppression therapies, it would be ideal to have a prodrug that would mitigate this property.
Prodrugs are new chemical entities which upon administration to the patient, regenerate the respective parent molecule within the body. Prodrug strategies or methodologies can be used to markedly enhance properties of a drug or to overcome an inherent deficiency in the pharmaceutical or pharmacokinetic properties of a drug. Various forms of prodrugs are well known in the art and are described in:
a) Wermuth, C. G. et al., The Practice of Medicinal Chemistry, Chapter 31, Academic Press (1996);
b) Bundgaard, H. ed., Design of Prodrugs, Elsevier (1985);
c) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991); and
d) Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism, Wiley-VCH (2003).
A myriad of Prodrug strategies exist which provide choices in modulating the conditions for regeneration of the parent drug, the physical, pharmaceutical or pharmacokinetic properties of the Prodrug, and the functionality to which the Prodrug modifications may be attached. The identification of prodrugs with desired properties is often difficult and is not straightforward.